recent pharmacology studies on the international … · recent pharmacology studies on the...

Recent Pharmacology Studies on the International Space Station

V. E. Wotring11 December 2014

https://ntrs.nasa.gov/search.jsp?R=20140017140 2018-08-27T04:43:35+00:00Z

Wotring JSC NASA Pharmacology 11 December 2014


Many physiological systems are affected by spaceflight

Medical Complaints in Space

Based on ISS Missions: AnorexiaSpace motion sicknessFatigueInsomniaDehydrationDermatitisBack painUpper respiratory infectionConjunctival irritationSubungual hemorrhageUrinary tract infectionCardiac arrhythmiaHeadacheMuscle strainDiarrheaConstipation

From Clement , Fundamentals of Space Medicine, 2003

Based on Space Shuttle,

1988‐ 1995Facial FullnessHeadacheSinus congestion

Dry skin, irritation, rashEye irritation, dryness, rednessForeign body in eyeSneezing/coughingSensory changesUpper respiratory infectionBack muscle painLeg/foot muscle painCutsShoulder/trunk muscle painHand/arm muscle painAnxiety/annoyanceContusionsEar problems (usu. Pain)Neck muscle painStress/tensionMuscle crampAbrasionsFever, chillsNosebleedPsoriasis, folliculitis, seborrheaLow heart rateMyoclonic jerks


Pharmaceutical Use on Shuttle



Our Mission at the JSC Pharmacology Lab…

…is to ensure that flight surgeons have good information about how administered pharmaceuticals will work in the extreme conditions of spaceflight…which means that we have to understand the physiological changes caused by living in the spaceflight environment…as well as the effect of the spaceflight environment on the stored drugs themselves…as well as the pharmaceuticals’ mechanism of action

Research in JSC Pharmacology

Pharmaceuticals • Usage tracking• StabilityPharmacokinetics• Absorption/Distribution• Metabolism/ExcretionPharmacodynamics• all the reasons medications are used


Medication Usage


How are medications usedon spaceflight missions? Retrospective Analysis of Medication Usage During Long Duration Spaceflight – a research study (PI: Wotring) that analyzes medication uses on past missions, conducted in partnership with occupational health efforts in JSC Pharmacy, directed by Dr. Tina Bayuse

Medication Usage


Dose Tracker Application for Monitoring Crew Medication Usage, Symptoms and Adverse Effects During Missions – a research study (PI: Wotring) that uses a specially designed iPad app for crew to record their medication uses.

Medication Usage



Human Exploration Research Analog (HERA)

The Human Exploration Research Analog is a two-story, four-port habitat unit. It is cylindrical with a vertical axis, and connects to a simulated airlock and hygiene module

Duration: 4-60 days Room Temperature: 72° F. (+/- 5 degrees)Light/Dark Cycle: Lights on 0600, lights out 2130, 7 days per week, no napping is permittedMonitoring of study operations 24 hours a day

Stability –How long is a medication safe and effective?

Flight‐aged medications that have been returned from the ISS by SpaceX Dragon are being analyzed for active pharmaceutical ingredient content and degradants/impurities (in‐house and in collaboration with FDA & academic experts; working with JSC Pharmacy)


Stability –How long is a medication safe and effective?

1. Evaluating packaging materials & methods to increase useful lifespan(working with JSC Pharmacy)

2. Low Gravity Drug Stability Analyzer (PI: Farquharson, Real Time Analyzers)


Stability‐How long is a medication safe and effective?

With non profit, academic and pharma partners, evaluating packaging materials & methods to increase useful lifespan, possibly even reformulation.


Health and Environmental Sciences InstituteMission: Engage scientists from academia, government, industry, research institutes, and NGOs to identify and resolve global health and environmental issues.

NASA Human Health and Performance Center (NHHPC) is a virtual center that brings organizations together to advance human health and performance innovations for life in space and on Earth by sharing best practices and engaging in collaborative projects.

Pharmacokinetics Does the spaceflight environment alter PK?

Inflight pharmacokinetic and pharmacodynamicresponses to medications commonly used in spaceflight, new research study (Wotring, Derendorf and Barger)


Pharmacokinetics‐Does the spaceflight environment alter PK?



PK Evidence: Flight studiesCintron & Putcha acetaminophen case studies, 1987

Salivary acetaminophen measured over time after oral administration of tablets (acetaminophen is the gold standard for examination of oral absorption, but substitution of saliva concentrations for plasma not established)

3 individuals ‐ each panel shows data from a single individual. Use of other medications is unspecified.

Two individuals show reduced peak concentration for FD1‐2 (middle and lower)One person shows slower absorption preflight, but this value is much slower than average ground values from the literature (0.8 h).

Paucity of data and variability in data preclude definitive conclusion.

PK Evidence: Bedrest studies



PK Evidence: Flight studies

Leach, et al., 96

Transient reduction in both volume and protein, that returns to almost normal values in a few days


PK Evidence: BedrestStudies

Lidocaine clearance increased by ~ 30% during 7 days of HDT.This suggests that hepatic metabolism is increased.

Lidocaine undergoes significant protein binding. An apparent change in clearance could be due to a change in protein binding. Data are mean ± SEM, n= 8 males. Mean data with large errors doesn’t distinguish between individuals with systematic (but varying degrees of changes) and high variability within subjects. Subjects were vertical for a short period on the morning of day 6. Lidocaine is a commonly used PK probe for hepatic metabolism. Bedrest has not been established as a good model for clearance. Saivin et al., 1995


PK Evidence: bedrest

Penicillin given IV before (closed symbols) and after (open symbols) 7 d supine bedrest, n=12, mean ±SEM. Supine, not HDT, but neither bedrest position has been shown to be a good model for spaceflight.

Kates et al., 1980

Bedrest has no effect on tubular secretion by kidney

Pharmacokinetics‐Does the spaceflight environment alter PK?

Inflight pharmacokinetic and pharmacodynamicresponses to medications commonly used in spaceflight, new research study (Wotring, Derendorf and Barger)



Sleep

Most medications used inflight are for sleep problemsInsufficient sleep leads to poor performance, both physically and

mentally, and has negative health effectsSleep aids like zolpidem and zaleplon increase sleep timeBut sleep aids with a long half‐life can impair next‐day

performance due to residual drug in the systemAnd in the event of an emergency that requires early awakening,

any sleep aid could impair performanceThe cause of inflight sleep disturbances is not understood. Melatonin and its analogs can be used to help set circadian

rhythms even in the absence of normal cues.


Lack of normal circadian cues probably contributes to sleep problems.

Turner & Mainster, 2008

Typical indoor ambient lighting is dimmer than most terrestrial indoor lighting (between 10‐100 lux on the middeck and in Spacelab) while the flight deck, with its large windows to the outside, experiences continual 90 minute cycles with highs of 1000 lux (sometimes almost 100,000) and lows of ~1 lux (Dijk et al.,2001).

This variability is not unlike the 15 min at 10,000 lux followed by 60 min at <3 lux cyclical paradigm found to have similar phase resetting properties as the same total time period of 10,000 lux (Rimmer et al.,2000).

Spaceflight lighting environment


Methods …crew members assigned to Space Transportation System shuttle flights with in-flightexperiments between July 12, 2001, and July 21, 2011, or assigned to International Space Station(ISS) expeditions between Sept 18, 2006, and March 16, 2011…wrist actigraphy, and subjectivesleep characteristics and hypnotic drug use via daily logs, in-flight and during Earth-based data-collection intervals…

Findings We collected data from 64 astronauts on 80 space shuttle missions (26 flights,1063 in-flight days) and 21 astronauts on 13 ISS missions (3248 in-flight days), with ground-based data from all astronauts (4014 days). Crew members attempted and obtained significantlyless sleep per night as estimated by actigraphy during space shuttle missions (7·35 h [SD 0·47]attempted, 5·96 h [0·56] obtained), in the 11 days before spaceflight (7·35 h [0·51], 6·04 h [0·72]),and about 3 months before spaceflight (7·40 h [0·59], 6·29 h [0·67]) compared with the firstweek post-mission (8·01 h [0·78], 6·74 h [0·91]; p<0·0001 for both measures). Crewmembers on ISS missions obtained significantly less sleep during spaceflight (6·09 h [0·67]),in the 11 days before spaceflight (5·86 h [0·94]), and during the 2-week interval scheduled about 3months before spaceflight (6·41 h [SD 0·65]) compared with in the first week post-mission (6·95h [1·04]; p<0·0001). 61 (78%) of 78 shuttle-mission crew members reported taking a dose of sleep-promoting drug on 500 (52%) of 963 nights; 12 (75%) of 16 ISS crew members reported usingsleep-promoting drugs.

Interpretation Sleep deficiency in astronauts was prevalent not only during space shuttle and ISSmissions, but also throughout a 3 month preflight training interval. Despite chronic sleepcurtailment, use of sleep-promoting drugs was pervasive during spaceflight. Because chronicsleep loss leads to performance decrements, our findings emphasise the need for

Prevalence of sleep deficiency and use of hypnotic drugs in astronauts before, during, and after spaceflight: anobservational studyLaura K Barger, Erin E Flynn-Evans, Alan Kubey, Lorcan Walsh, Joseph M Ronda,Wei Wang, Kenneth P Wright Jr, Charles A Czeisler (Lancet Neurology 2014)


Dura

tion

of sl

eep (

h)

10 * *

*

9

8

7

6

5

4

0 90 days before launch 11 days before launch In-flight 7 days after return to Earth

Figure 1: Mean sleep duration before, during, and after shuttle missions Horizontal lines within box plots show the median value for each interval based on means for each participant; the 25th and 75th percentiles are represented by the bottom and top of the box, respectively, and the 10th and 90th percentiles as error bars. The dots represent individual participants with means lower than the 10th or higher than the 90th percentile. *Mean sleep duration was less during the two preflight periods and in-flight than in the 7-day post-flight interval (adjusted p<0·0001 for all three comparisons).


Sleep deprivation has cognitive effects

The two images above show areas of the brain where blood flow decreases when a person is deprived of sleep for 24 hours, compared with when they are rested. Researchers suspect that reduced blood flow in such areas as the prefrontal cortex, located toward the front of the head (the top of each image), may be linked to deficits in concentration and other kinds of cognitive performance that are noted in people who have lost a lot of sleep. SfN, Brain Briefings, Summer 2008

Inflight pharmacokinetic andpharmacodynamic

responses to medications commonly used in spaceflight


Dura

tion

of sl

eep (

h)

10 * *

*

9

8

7

6

5

4

0 90 days before launch 11 days before launch In-flight 7 days after return to Earth

Figure 1: Mean sleep duration before, during, and after shuttle missions Horizontal lines within box plots show the median value for each interval based on means for each participant; the 25th and 75th percentiles are represented by the bottom and top of the box, respectively, and the 10th and 90th percentiles as error bars. The dots represent individual participants with means lower than the 10th or higher than the 90th percentile. *Mean sleep duration was less during the two preflight periods and in-flight than in the 7-day post-flight interval (adjusted p<0·0001 for all three comparisons).

Study will include measures of sleep and ultrasounds, in addition to standard pharmacokinetic measures (circulating drug concentrations over time).


The eight holes on this chip are ports that can be filled with fluids or chemicals. Tiny valves control the chemical processes by

mixing fluids that move in the tiny channels that look like lines, connecting

the ports.

Samples must be returned to Earth for analysis currently, but in the future, lab-on-a-chip methods could enable inflight analysis.

Bone

How can medications be used to prevent or reduce spaceflight‐induced bone loss?

Bisphosphonates proven effective inflight.

Watching new osteoporosis treatments, denosumab, teriparatide, various others …


Bisphosphonates Bisphosphonates' mechanisms of action all stem from their structures'

similarity to pyrophosphate , a component of bone. Bisphosphonates, when attached to bone tissue, inhibit osteoclasts, the bone

cells that break down bone tissue.

Bisphosphonates

Muscle Atrophy

How can medications be used to prevent or reduce spaceflight‐induced muscle atrophy?

• Watching selective androgen receptor modulators, mostly in pre‐clinical trials



Testosterone is an anabolic steroid

Changes from Base Line in Mean (SE) 10 Weeks of Treatment. The P values shown are for the comparison between the change indicated and a change of zero. The asterisks indicateP0.05 for the comparison between the change indicated and that in either no‐exercise group; the daggers, P0.05 for the comparison between the change indicated and that in the group assigned to placebo with no exercise; and the double daggers, P0.05 for the comparison between the change indicated and the changes in all three other groups.

Bhasin et al., 1996

Testosterone treatment resulted in increased muscle mass and strength

Testosterone binds androgen receptors, nuclear receptors that initiate gene expression. Androgen receptors are found in many tissues: muscle, prostate, brain, skin, etc.

Because testosterone has effects on many tissues, its therapeutic use (to improve muscle mass) is linked to effects on reproductive organs, mood, behavior, blood lipids, other organs.


Selective androgen receptor modulators (SARMs)

Page et al., 2008

24 weeks of treatment (implanted pump), n=28 male rats per group

A new steroid analog 19‐Nor‐4‐Androstenediol‐3,17‐Diol (3,19‐NA) increases muscle (and bone mineral density, not shown) without affecting reproductive tissues

3,19‐NA increases muscle without affecting reproductive tissues


~ 70 % of crew experience SASIn the top 4 reasons for inflight medication useIncludes nausea, pallor, cold sweating, and sometimes vomiting

Generally occurs during periods of environmental transition, in either the first few days of flight, or the first few days back on Earth, or both

SAS symptoms and/or Rx side effects limit crew activities flight day 1‐3 and again at landing.

Space Adaptation Syndrome

Space Adaptation Syndrome

How can medications be used to treat or prevent space adaptation syndrome?

• Can a training protocol permit reduced dependence on medication? (PI: Young)



The rotating chair has a maximum velocity up to 360 degrees/second .www.graybiel.brandeis.edu/.../facilities.html

Motion sickness is used to model space motion sickness


Pharmacological intervention sites for SAS

after Nachum et al., 2006

H1 H1

5HT3 D2

NK1

5HT35HT3

mAch

mAchmAch


Not all antiemetics are effective against rotation‐induced illness

Levine et al., 2000

Self‐ratings of illness with ondansetron are no different than with placebo.

Ondansetron is the 5HT3 antagonist antiemetic that revolutionized cancer chemotherapy,

N=12, double-blind, repeated measures, 1 week intervals, rotating drum stimulus.


Not all antiemetics are effective against wave‐induced illness

data from Hershkovitz et al., 2009

N=16 sailors prone to seasickness in double‐blind, cross‐over design, on two voyages with similar sea conditions

Self‐ratings of illness with ondansetron are no different than with placebo


Neurokinin antagonists are ineffective against motion‐induced illness

0

100

200

300

400

NK1 antag NK1 antag+ 5HT3antag

Scopolamine Placebo

Motion Stim

ulus Tolerated

data from Reid et al., 2000

N=16, double-blind, randomised, crossover design; stimulus was a rotating chair, subjects performed head movements during rotation; trials were stopped at subject report of Malaise

Neurokinin antagonists are ineffective against motion‐induced illness


Promethazine and Scopolamine are the best currently available motion sickness

treatments

Dornhoffer et al., 2004

Both PMZ and Scop permit increased rotation tolerance; antihistamines are ineffective

N=15 per group, each participant was randomly given placebo or one of the study drugs, sessions separated by 2 weeks


Reduction in severe SAS after introduction of PMZ

Davis et al., 1993

0

10

20

30

40

50

60

Mild Moderate Severe

Scopalamine

After PMZ

PMZ reduced severe SAS on STS flightsSelf‐reports of symptom severity before and after the introduction of promethazine for SMS

on STS missions. N=26 (after).

Vision and Intracranial Pressure Changes

New issue – hasn’t been well defined yet

• Are medications involved in vision and intracranial pressure changes seen in spaceflight? (Data mining study in progress, PI Wotring)

• Investigating treatment options


Radioprotectants

How can medications be used to prevent or reduce physiological effects of radiation exposure?

— Watching antioxidants, as well as other more selective compounds, in pre‐clinical trials.


General NASA info: http://www.nasa.gov

Human Research at NASA: http://humanresearch.jsc.nasa.gov/NASA Research Grants http://nspires.nasaprs.com/external/NSBRI http://www.nsbri.org/Bedrest Study Info: http://www.bedreststudy.comPostdoctoral Opportunities http://nasa.orau.org/postdoc/Don Pettit’s Blog http://blogs.airspacemag.com/pettit/

Ginger [email protected]

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